2-Aminotetralin derivatives for the therapy of glaucoma

ABSTRACT

The use of racemic or optically active compounds represented by formula (I) and the salts thereof wherein R is H or CH 3  for the preparation of pharmaceutical compositions for the therapy of ophthalmic disorders.

The present invention relates to the use of racemic or optically activecompounds represented by formula I and the salts thereof

wherein R is H or CH₃,

for the preparation of pharmaceutical compositions for the therapy ofophtalmic disorders.

More particularly, the invention relates to the use of(±)-(R,S)-5,6-diisobutyroyloxy-2-methylamino-tetralin or its(−)-(S)-enantiomer in the preparation of ophthalmic formulations for thetreatment of glaucoma.

Glaucoma is an ophthalmic disorder characterized by increasedintraocular pressure which causes excavation and degeneration of theoptic disc. Notwithstanding the therapeutical progresses attained,glaucoma, whose etiology has not yet been completely clarified, is oneof the main causes of irreversible blindness.

Three types of glaucoma are known: primary, secondary and congenitalglaucoma. Primary glaucoma is, in turn, classified in acute congestiveor angle-closure glaucoma and simple chronic or open-angle glaucoma. Thehigh intraocular pressure (IOP) is due to insufficient outflow of theaqueous humour from the eye anterior chamber. Therefore, the symptomatictherapy usually aims at decreasing the intraocular pressure, which canbe attained via three mechanisms: i) increasing of the outflow ofaqueous humor by use of direct parasympathomimetic or cholinesteraseinhibitors; ii) dehydration of the eye bulbs by use of osmotic agentssuch as urea or mannitol; iii) reduction in the aqueous humor productionby the ciliated epithelium: a number of medicaments, such as carbonicanhydrase inhibitors and β-blockers, act according to this mechanism.

The medicaments of the various classes cited above can be administeredeither alone or in combinations thereof.

Sympathomimetics have been widely used in the past, mainly in thetreatment of open-angle glaucoma. These drugs act either through directstimulation of adrenergic receptors or through release of catecholaminesfrom the synaptic vesicles of the adrenergic nerve terminals. Theydiffer both in their selectivity towards specific receptors and in theintensity of the adrenergic responses they give rise to. Depending onthe type of receptors preferably involved, they can act either bypromoting the outflow of aqueous humor or by decreasing its production.However, such drugs induce a number of side effects mainly connectedwith their aspecificity, therefore the use of such medicaments asadrenaline or its corresponding pro-drug dipivefrin is restricted to acombination therapy in patients in which β-blockers are contraindicated.In order to decrease the onset of side effects, research has beenfocused on drugs with higher selectivity, particularly towardspre-synaptic α₂-adrenoceptors. α₂-Agonists act both by promoting theoutflow of aqueous humor and by decreasing its production. Two Clonidineanalogues belonging to this pharmacological class, namely Brimonidineand Apraclonidine, have recently been introduced in therapy. The searchfor drugs for the treatment of glaucoma is also directed to dopamineanalogues for their capability of stimulating α-adrenoceptors inaddition to the dopaminergic ones. By virtue of this dual action, thedecrease in intraocular pressure can take place through a plurality ofmechanisms of action. In many experimental studies some DA₂-agonistswere found particularly active; since they induce inhibition ofcatecholamines release in the eye, they can be functionally consideredas indirectly acting β-blockers. Among dopaminergic medicaments, anumber of aminotetralin derivatives have been the object of severalstudies and Patent applications.

Burke J et al. (J. Auton. Pharmac. 4, 185-192, 1984) report that6,7-dihydroxy-2-aminotetralin andN,N-dimethyl-6,7-dihydroxy-2-aminotetralin, administered as ophthalmicdrops, gives rise to eye hypotension in the rabbit. A subsequent study,carried out on the same experimental model by Thörig L et al.(Ophthalmic Res. 17, 362-372, 1985) showed thatN,N-dimethyl-5,6-dihydroxy-2-aminotetralin (M-7) is active as well inreducing intraocular pressure but induces eye irritation already at aconcentration of 0.1%. In a general way catechol derivatives arecharacterized by inherent stability problems which could adverselyaffect their successful pharmaceutical employment. Moreover thepartition coefficient (logP_(app)) of 2-amminotetralins with thecatechol group free is usually not optimal for ocular absorption(Schoenwald R D et al. J. Pharm. Sci. 72, 1266-1272, 1983 and J. Pharm.Sci. 67, 787-789, 1978).

U.S. Pat. No. 4,588,747 in the name of Synthelabo claims the use ofN,N-propyl-6-hydroxy-formylamino-2 aminotetralins.

U.S. Pat. No. 4,657,925 in the name of Nelson R & D claims the use ofvariously substituted N-alkyl, N-arylalkyl-2-aminotetralins, acting onDA₂ receptors. More particularly, the use of2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin is claimed. Saidderivative however, although exerting a long-lasting action, can alsoinduce eye irritation.

U.S. Pat. No. 4,722,933, in the name of Alcon, claims the use of5,6-acyloyloxy-1-hydroxy-2-aminotetralin derivatives lacking sideeffects on the cardiovascular system.

U.S. Pat. No. 5,382,596, EP 163458, U.S. Pat. No. 5,430,056, EP 627407,U.S. Pat. No. 5,140,040, U.S. Pat. No. 5,086,074 claim otheraminotetralin derivatives utilizable in a number of pathologies,including glaucoma, which could benefit from a treatment based ondopaminergic medicaments. Said documents report no data supporting theeffectiveness in the treatment of said disease.

None of these compounds has to-date been introduced in therapy.Therefore, a need exists for aminotetralin derivatives for the treatmentof glaucoma which provides for potent control of elevated IOP withoutcausing significant side effects, especially on the cardiovascularsystem. In particular, a need exists for derivatives with good localtolerability and topical bioavailability, soluble as well stable inaqueous medium and which do not show tolerance upon prolongedadministration.

OBJECT OF THE INVENTION

(±)-(R,S)-5,6-diisobutyryloxy-2-methylaminotetralin, (from now onreferred to as CHF 1035), was first disclosed in GB 2,123,410 among aseries of potentially antibronchospastic aminotetralin derivatives;afterwards the use of said compound in the treatment of cardiacdisorders, particularly congestive heart failure, was claimed.

It has now been found that CHF 1035 can be effectively used in thetreatment of glaucoma through the topical administration.

Studies carried out in normotensive rabbits as well as in rabbits withwater-increased IOP showed that CHF 1035 in the form of ophthalmic dropssignificantly decreases, after single administration, the intraocularpressure.

As regards to the study in normotensive rabbits, advantageously,compared to brimonidine, no significant IOP decrease was observed in theuntreated eye, indicating that very little or no systemic absorptionoccurred. In comparison to said reference compound, CHF 1035 exhibits aless rapid onset of action, but a longer duration of action.

Further results prove that CHF 1035 induces a persistent decrease in IOPafter repeated administrations.

The 5,6-diisobutyroyloxy-2-methylamino-tetralin derivative, comparedwith the compound with the free catechol group at the 5,6 position orwith other similar compounds (M-7), has better characteristics in termsof chemical stability and ocular bioavailability, as proved by thehigher partition coefficient n-octanol/buffer pH 7.4 (logP_(app)=0.75vs. −0.9). The better chemical stability, makes the handling of thestarting material easier and also allows to prepare solutions for theophthalmic use with pH nearer to the physiological values and thereforebetter tolerated.

Furthermore, it has surprisingly been found that, contrary to whatstated in the prior art (Järvinen T et al. Adv. Drug Deliv. Rev. 1996,19, 203-224), the protection of the catechol group through formation ofthe corresponding diisobutyroyloxy derivative, besides improving cornealpermeability, also increases the ocular tolerability of the drugs. Themedicament is indeed well tolerated up to 5% concentration, causingneither irritation symptoms such as redness and blinking, nor otherundesired side effects. Chetoni P et al. Int. J. Pharm. 105, 147-155,1994 report that in case of, for example, albuterol, the synthesis ofthe corresponding esterified pro-drug, although increasingeffectiveness, does not prevent its irritant effects. Dipivefrin, whichhas been introduced on the market as a pro-drug of adrenaline in theform of dipivaloyl ester, gives rise to side effects such as pain in theeye and in the superciliary arch as well as corneal vascularization andopacification during long-term use. (Salminen L et al. J. Ocul.Pharmacol. Ther. 11, 37-40, 1995). The in vivo use of the prodrugs ofpilocarpine is associated with ocular irritation (Saarinen-Savolainen Pet al. Int. J. Pharm. 133, 171-178, 1996; Suhonen P et al. Int. J.Pharm. 127, 85-94, 1996).

For its favorable characteristics, CHF 1035 can be advantageously usedfor the preparation of compositions for the ophthalmic use in thetherapy of glaucoma. Even more preferred is the use of the corresponding(−)-(S) enantiomer which is about twice as much selective towards the α2and DA₂ receptors than the racemate.

The present invention, besides CHF 1035, also includes the analogousderivative without the methyl group on the amino group. The compounds ofthe invention can be used in the form of salts with inorganic acids,such as hydrochloride and hydrobromide, or with organic acids such asacetate, tartrate and citrate.

The amount of active ingredient to be used will vary with the age of thepatient and the severity of the glaucoma.

Generally, the concentration of the active ingredient will range from0.001 to 5%, preferably between 0.01 and 1.0%.

For the ocular administration, the compounds can be formulated asaqueous solution or in the form of ointments, creams or gels, by usingthe conventional additives and excipients.

Preferred carriers for the compounds of the invention are thoseconsisting of a sterile isotonic aqueous solution, for theadministration in the form of ophthalmic drops, containingviscosity-increasing agents such as hydroxypropylmethylcelluose,stabilizing agents such as EDTA or sodium bisulfite, preservatives suchas benzalkonium chloride or chlorobutanol.

Advantageously, the pH of the opthalmic composition will be adjustedbetween 3.0 to 7.5 by using conventional buffering agents such asborates, carbonates or phosphates. Preferably it will be adjustedbetween 4.0 and 5.0 avoiding buffers in order to manipulate thephysiological environment of precorneal area as little as possible.

The invention is illustrated in detail by the following examples.

EXAMPLE 1 Determination of Apparent Partition Coefficient

The apparent partition coefficients (log P_(app)) of CHF 1035 weredetermined from the distribution of the compound between 1-octanol andphosphate buffer solution (50 mM; pH 1.4, 5.5, 6.5 and 7.4). Thephosphate buffer solution and 1-octanol were saturated with each other,prior to partition study, by shaking vigorously for 24 h. A knownconcentration of CHF 1035 in the phosphate buffer solution was shaken 60minutes with suitable volume of saturated 1-octanol. After shaking, thephases were separated by centrifugation, and the concentrations of CHF1035 in the buffer phase were determined by HPLC before and afterpartitioning. The results expressed as a mean±SD (standard deviation)are reported in Table 1.

TABLE 1 Apparent partition coefficient (log P_(app), mean ± SD, n = 3)of CHF 1035. pH of buffer solution Log P_(app) (mean ± SD, n = 3) 4.50.17 ± 0.02 5.5 0.17 ± 0.01 6.5 0.20 ± 0.08 7.4 0.75 ± 0.02

CHF 1035 is a base with pKa=9.4, so its log P_(app) value increases withincreased pH. The higher apparent partition coefficient would be morefavorable for ophthalmic absorption. However, an acid aqueous solutionshould be used as a vehicle for eyedrop administration due to the betterchemical stability of CHF 1035 in such pH range. The theoretical logP_(app) of the corresponding not esterified derivative turned out to be−0.9 at pH 7.4.

EXAMPLE 2 Intraocular Pressure (IOP) Studies After Single Dose inNormotensive Rabbits

Water (pH 4.5, made isotonic with sodium chloride), was selected asvehicle for the IOP-studies. Buffer solution was not used in order tomanipulate the physiological environment of precorneal area as little aspossible. pH 4.5 was selected to confer a good stability to CHF 1035.

Five concentrations (0.01, 0.05, 0.2, 0.5 and 1.0% w/v) of CHF 1035 werestudied. Brimonidine (0.2% w/v) was used as a positive, and vehicle(water pH 4.5) as a negative control.

The experimental animals used were normotensive Dutch Belted rabbits ofeither gender (n=6). A single drop (25 μl) of the test solution wasinstilled unilaterally into the left eye (treated eye). IOP of therabbits (treated and untreated eyes) was measured at 1 and 0 h before,and at 0.5, 1, 2, 3, 4, 5, 6 and 7 h after topical eyedropadministration. IOP at the time of eyedrop administration (0 h) was usedas a baseline value. IOP was measured using a BioRad Pneumatonometer.More detailed description of the IOP measurement procedure can be foundin Pharm. Res. 14, 1738-1743, 1997 and Curr. Eye Res. 14, 791-797, 1995.All the studies were set up using a randomized crossover design. Atleast 72 h of wash-out time was allowed for each rabbit between dosings.The irritation caused by an instilled eyedrop were evaluated byrecording the extent of eyelid closure after topical eyedropadministration.

The effects expressed as change from baseline (mmHg) are reported inTable 2 and 3 as mean±SEM (standard error of mean).

CHF 1035 decreases significantly the IOP in the treated eye aftertopical administration into normotensive rabbits. However, nosignificant IOP decrease is observed in the untreated eye, which isconsidered to be a benefit. The minor IOP effects in untreated eye maymean minor systemic absorption and decreased risk for serious systemicside-effects.

CHF 1035 shows a late onset of action which may be caused by itsprodrug-nature. The maximum decrease in IOP occurs between 5 and 6 hwith doses between 0.2% and 1.0%. In cases of smaller doses (i.e., doses0.01% and 0.05%), the maximum decrease in IOP tends to be earlier. Theprodrug-nature may also prolong the duration of action of CHF 1035.

Topical administration (single dose) of CHF 1035 did not causesignificant eye irritation in rabbits: no eyelid closure was observedafter topical administration (25 μl) of 0.5%, 0,2%, 0.05% and 0.01% CHF1035 solution.

CHF 1035 also turned out to be more effective in decreasing IOP thanbrimonidine, and has longer duration of action than brimonidine.

No significant IOP changes was observed after vehicle administration:the IOP change was between −1.1 and 1.4 mmHg, and between 0.3 and 1.5mmHg in the treated and in the untreated eye, respectively.

TABLE 2 Intraocular pressure (IOP) changes (mean mmHg ± SEM) in thetreated eye of normotensive rabbits (n = 6) after unilateraladministration of test solution. TIME (min) DOSE (%, w/v) 0 30 60 120180 240 300 360 420 water* 0.0 ± 0.0 0.7 ± 0.4 −0.9 ± 0.4 −0.3 ± 0.6  0.0 ± 0.6 −0.2 ± 0.5   0.0 ± 0.7 −0.4 ± 0.9   0.6 ± 0.9  1.0% CHF 0.0± 0.0 1.3 ± 0.9   0.4 ± 1.0   0.1 ± 0.9 −3.2 ± 1.8 −4.9 ± 1.5 −5.8 ± 1.6−6.6 ± 1.6 −5.3 ± 1.5  0.5% CHF 0.0 ± 0.0 1.8 ± 0.6   1.2 ± 0.7   0.1 ±0.7 −5.0 ± 1.2 −5.6 ± 0.6 −7.9 ± 0.9 −6.9 ± 0.8 −7.0 ± 0.8  0.2% CHF 0.0± 0.0 0.8 ± 0.9 −0.4 ± 1.1 −2.1 ± 0.7 −6.0 ± 0.9 −6.3 ± 1.0 −7.6 ± 1.5−6.9 ± 1.0 −5.7 ± 1.1 0.05% CHF 0.0 ± 0.0 −0.4 ± 0.5   −3.3 ± 0.4 −6.5 ±0.9 −6.3 ± 0.9 −6.7 ± 0.8 −6.4 ± 0.8 −5.5 ± 0.7 −4.3 ± 0.5 0.01% CHF 0.0± 0.0 −1.9 ± 0.9   −4.2 ± 1.1 −5.3 ± 0.7 −5.0 ± 1.0 −4.5 ± 1.3 −4.3 ±0.9 −2.6 ± 0.6 −1.3 ± 0.8  0.2% Brim. 0.0 ± 0.0 −2.7 ± 0.9   −7.8 ± 0.9−6.2 ± 1.4 −3.9 ± 0.8 −3.4 ± 0.7 −2.4 ± 0.7 −0.4 ± 0.6   0.2 ± 0.3 *= nequals 12(2 × 6) instead of 6 CHF = CHF 1035 HCl Brim. = Brimonidine

TABLE 3 Intraocular pressure (IOP) changes (mean mmHg ± SEM) in theuntreated eye of normotensive rabbits (n = 6) after unilateraladministration of test solution. TIME (min) DOSE (%, w/v) 0 30 60 120180 240 300 360 420 water* 0.0 ± 0.0 0.3 ± 0.5 −0.4 ± 0.3   0.0 ± 0.5−0.2 ± 0.4 −0.4 ± 0.4 −0.7 ± 0.7   0.3 ± 0.8 0.9 ± 0.4  1.0% CHF 0.0 ±0.0 2.2 ± 0.9 1.2 ± 1.2 1.0 ± 0.8 −2.5 ± 1.3 −1.8 ± 0.6 −0.7 ± 0.8 −0.2± 1.1 −0.9 ± 1.0    0.5% CHF 0.0 ± 0.0 2.9 ± 0.8 2.4 ± 0.7 1.4 ± 0.4  0.0 ± 0.5 −0.2 ± 0.7 −0.9 ± 0.4 −0.7 ± 0.6 −0.2 ± 0.3    0.2% CHF 0.0± 0.0 1.0 ± 0.8 0.5 ± 1.2 0.0 ± 0.9 −1.5 ± 1.2 −1.6 ± 1.1 −1.1 ± 1.1−0.7 ± 1.0 0.0 ± 0.8 0.05% CHF 0.0 ± 0.0 0.0 ± 0.6 0.1 ± 0.7 −1.5 ±0.8   −0.4 ± 1.0 −1.0 ± 0.4 −1.9 ± 0.9 −0.6 ± 1.2 0.3 ± 0.7 0.01% CHF0.0 ± 0.0 −1.0 ± 1.1   −1.9 ± 1.2   −1.6 ± 1.0   −0.5 ± 0.7 −1.4 ± 0.7−1.7 ± 0.4   0.0 ± 0.6 0.4 ± 0.7  0.2% Brim. 0.0 ± 0.0 −3.2 ± 1.2   −8.7± 0.8   −3.3 ± 1.3   −1.7 ± 0.9 −2.1 ± 1.0 −0.6 ± 0.9   0.1 ± 0.6 0.0 ±0.6 *= n equals 12(2 × 6) instead of 6 CHF = CHF 1035 HCl Brim. =Brimonidine

EXAMPLE 3 Intraocular Pressure (IOP) Studies After Single Dose inRabbits with Water-increased IOP

A study versus placebo was carried out in 20 New-Zealand albino rabbitsto evaluate the effects of CHF 1035 after single administration. Basalintraocular pressure (IOP) was measured in anaesthetized rabbits in botheyes. Each eye received two drops of physiological solution containing5% of the drug. Control animals received only physiological solution.After one hour, the animals were administered by oral route with a totalamount of 200 ml of distilled water. IOP increased within about one hourand normalized after about 3 hours. As no differences in IOP wereobserved between the two eyes, the respective tonometric curves weresuperimposed. IOP measurements were carried out by using a Goldmantonometer and were repeated one hour after the administration of water.

FIG. 1 shows the effect of CHF 1035 on rabbit intraocular pressure (IOP)after water loading. Values are expressed as mean (SE¹32 1.6-2.7). Thetotal number of eyes per group is in brackets.

It can be appreciated that the animals pre-treated with CHF 1035 show anIOP value significantly lower than control animals.

¹ Standard error

EXAMPLE 4 Intraocular Pressure (IOP) Studies After RepeatedAdministration in Rabbits with Water-increased IOP

The effectiveness of CHF 1035 after repeated administration was testedin a study versus placebo, in 20 New-Zealand albino rabbits. In order toinduce a chronic increase of the IOP, each animal was intraocularlyinjected with 0.5 mg/day of α-chymotrypsin for five days. Starting fromthe first day of treatment, two drops of physiological saline containing5% of the drug were instilled in each eye every 6 hours. The controlanimals only received physiological saline.

The IOP measurement was performed as described in example 1, before theinjection and subsequently every day until the 10^(th) day.

FIG. 2 reports the effect of CHF 1035 on rabbit IOP after α-chymotrypsininjection. Values are reported as mean (SE=1.2-2.6; n=20 per group).

IOP values are similar before the injection of α-chymotrypsin. However,the animals treated with CHF 1035 showed significantly lower IOP thananimals treated with placebo. Moreover, the medicament turned out to bewell tolerated during the whole cycle of treatment and induced no eyeirritation and/or discomfort.

1. A method of treating glaucoma, comprising administering to an eye inneed thereof an effective amount of at least one compound of formula I,enantiomers thereof, and salts thereof:

to treat the glaucoma; wherein R is H or CH3.
 2. The method of claim 1,wherein R is H.
 3. The method of claim 1, wherein R is CH3.
 4. Themethod of claim 3, wherein the compound of formula I is(−)-(S)-5,6-diisobutyroyloxy-2-methylamino-tetralin.
 5. The method ofclaim 1, wherein the at least one compound is administered incombination with one or more suitable carriers.
 6. The method of claim1, wherein the at least one compound is formulated as an aqueoussolution.
 7. The method of claim 6, wherein the at least one compound ispresent in a concentration of from 0.001 to 5%.
 8. The method of claim6, wherein the at least one compound is present in a concentration offrom 0.01 to 1%.
 9. The method of claim 1, wherein the at least onecompound is formulated as an ointment.
 10. The method of claim 9,wherein the at least one compound is present in a concentration of from0.001 to 5%.
 11. The method of claim 9, wherein the at least onecompound is present in a concentration of from 0.01 to 1%.
 12. Themethod of claim 1, wherein the at least one compound is formulated as acream.
 13. The method of claim 12, wherein the at least one compound ispresent in a concentration of from 0.001 to 5%.
 14. The method of claim12, wherein the at least one compound is present in a concentration offrom 0.01 to 1%.
 15. The method of claim 1, wherein the at least onecompound is formulated gel.
 16. The method of claim 15, wherein the atleast one compound is present in a concentration of from 0.001 to 5%.17. The method of claim 15, wherein the at least one compound is presentin a concentration of from 0.01 to 1%.